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While his brother Lorenzo took on the role of a statesman, Giuliano was something of a playboy, becoming known for his jousting tournaments and handsome physique.
On April 26, 1478, Giuliano attended High Mass in Florence with his mistress, and his brother Lorenzo. However, before they could enter the Santa Maria del Fiore, they were attacked by the Pazzi conspirators.

Bernardo Baroncelli delivered the first blow, and slashed Guiliano in the chest. As Francesco de' Pazzi advanced on him, Guiliano begged for mercy, but Francesco refused, and stabbed him nineteen times in the chest, killing him.

A month after Giuliano's death, his son Giulio was born. Giulio was considered legitimate due to a loophole in Canon law, allowing marriages to occur privately between two people. This meant that parents could have agreed that they were married without informing anyone. Giulio later became Pope Clement VII.